Functions of secreted Wnt inhibitors in hair follicle patterning and regenerative activity

分泌型 Wnt 抑制剂在毛囊模式形成和再生活性中的功能

基本信息

批准号：
10625345
负责人：
Alicia Ho
金额：
$ 4.61万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625345
关键词：
Acceleration Adult Affect Alleles Apoptosis Biological Assay Biological Models Biology Characteristics Communication Cre lox recombination system Data Dermal Dermis Development Differentiation Antigens Disease Doctor of Philosophy Dorsal Doxycycline Ear Embryo Embryonic Development Environment Exhibits Fellowship Female Gene Deletion Gene Expression Genes Genetic Goals Growth Growth Disorders Hair Hair follicle structure Heterogeneity Heterozygote Histology Human Immunofluorescence Immunologic In Situ Hybridization Knockout Mice Life Ligands LoxP-flanked allele Male Pattern Baldness Mentorship Miniaturization Molecular Morphogenesis Mus Pathway interactions Pattern Phase Play Process Proliferating Property Regenerative capacity Regenerative research Research Role Scalp structure Science Signal Pathway Signal Transduction Skin Skin Pigmentation Techniques Testing Therapeutic Thick Thinness Time Training Variant Woman Work base beta catenin career density experience experimental study external ear auricle hair regeneration improved inhibitor men mutant new therapeutic target novel therapeutic intervention novel therapeutics postnatal psychologic regenerative regional difference research and development single-cell RNA sequencing skin disorder skin organogenesis social tongue papilla

项目摘要

PROJECT SUMMARY Different regions of skin exhibit distinct properties and functions, including their patterns of hair follicle distribution and regenerative properties. Hair loss diseases often have regional effects due to this variation in skin biology. An extremely common example in both men and women is androgenetic alopecia, or AGA, also known as male pattern baldness and female pattern hair loss. AGA affects only scalp hair, and is characterized by disruption of signaling in and around the hair follicle (HF) that leads to inhibition of the hair growth cycle and hair follicle miniaturization. Hair loss diseases can have negative psychological, social, and financial impacts. Current treatments are only partially effective, and the molecular basis for regional variation in skin and hair growth is not well-characterized. Delineating the mechanisms underlying skin and hair heterogeneity has the potential to identify improved therapeutic approaches to hair loss and skin diseases. Wnt/β-catenin signaling is crucial for the initiation, development, and regeneration of hair, and can be modulated by endogenous secreted Wnt inhibitors. Dkk2 and Sostdc1 are secreted Wnt inhibitors that have regionally distinct expression patterns, with relatively higher expression levels in regions of embryonic mouse skin that develop poorly regenerative hair follicles or remain completely hairless. Preliminary data show that Dkk2 and Sostdc1 are also upregulated in the dermal papilla of postnatal HFs as the anagen growth phase ends. The proposed research will test the global hypothesis that Dkk2 and Sostdc1 dictate whether skin will be hair-bearing, determine HF size and regenerative capacity, and control adult HF cycling. Aim 1 will delineate the roles of Dkk2 and Sostdc1 in HF patterning during embryogenesis using Dkk2/Sostdc1 global null mice. Aim 2 will determine the postnatal functions of these inhibitors in regulating HF size and cycling independent of their embryonic roles by inducing deletion postnatally in Dkk2/Sostdc1 floxed mice. Successful completion of the proposed aims has the potential to identify novel therapeutic targets for hair loss diseases and will provide the candidate with rigorous training in experimental techniques and science communication that is essential for an independent research career. Supplemented with the proposed mentorship experiences and collaborative intellectual environment, this fellowship will accelerate the career progress of a promising PhD Candidate who is strongly committed to skin development and regeneration research.

项目概要皮肤的不同区域表现出不同的特性和功能，包括毛囊的模式由于这种差异，脱发疾病通常具有区域性影响。皮肤生物学中一个在男性和女性中极为常见的例子是雄激素性脱发（AGA）。 AGA 被称为男性型脱发和女性型脱发，其特征仅影响头皮毛发。通过破坏毛囊 (HF) 内和周围的信号传导，导致毛发生长周期受到抑制，毛囊微型化可能会产生负面的心理、社会和经济影响。目前的治疗方法仅部分有效，皮肤和头发区域差异的分子基础生长的特征尚不明确。确定改进的 Wnt/β-连环蛋白信号传导治疗方法的潜力很大。对于头发的起始、发育和再生至关重要，并且可以通过内源性分泌物调节 Wnt 抑制剂 Dkk2 和 Sostdc1 是具有区域不同表达模式的分泌型 Wnt 抑制剂。在再生能力较差的胚胎小鼠皮肤区域中表达水平相对较高初步数据显示，Dkk2 和 Sostdc1 也上调。当生长期生长阶段结束时，在出生后 HF 的真皮乳头中。 Dkk2 和 Sostdc1 决定皮肤是否有毛发、决定 HF 大小和目标 1 将描述 Dkk2 和 Sostdc1 在 HF 中的作用。使用 Dkk2/Sostdc1 全局无效小鼠的胚胎发生过程中的模式将确定出生后。这些抑制剂在调节 HF 大小和周期方面的功能独立于其胚胎作用，通过诱导 Dkk2/Sostdc1 floxed 小鼠出生后删除成功完成了拟议的目标。有潜力确定脱发治疗疾病的新靶点，并将为候选人提供严格的实验技术和科学传播方面的培训对于独立研究至关重要补充建议的指导经验和协作智力环境，该奖学金将加速有前途的博士候选人的职业进步，他坚定地致力于皮肤发育和再生研究。